Basic esters of cyclohexylideneacetic acids and intermediates

ABSTRACT

Cyclohexanone, optionally substituted in the 2-position by lower-alkyl and/or in the 4-position by hydroxy or acyloxy, reacts with a trilower-alkyl Alpha -phosphono-lower-alkanoate to give a lower-alkyl Delta 1, -cyclohexaneacetate or corresponding derivative thereof. The latter is hydrolyzed to the free acid, which, via the acid chloride, is esterified with an amino-lower-alkanol, giving basic esters having cardiovascular and antidepressant properties.

O Umted States Patent [1113,624,127

[72] Inventors Philip E. Shaw 56] R f rences Cited Winter Haven, Fl8.;FORElGN PATENTS Sol D All) zg k Y L Cmke 6,505,232 10/1965 Netherlands260/468 [2]] pp No 585 759 1,429,993 1/1966 France 260/468 [22] FiledOct, 1966 1,439,315 4/1966 France 260/468 s [45] Patented Nov. 30, 1971Primary Examiner-Lewis Colts [73] Assignee Sterling Drug lnc. AssistantExaminer- Paul J. Killos New York, N.Y. Atl0rneys Elmer J. Lawson, B.Woodrow Wyatt, Thomas L. Johnson, Robert K. Bair, R. Clifford Bourgeois,William G. Webb and Ro er T. Wolfe [54] BASIC ESTERS OFCYCLOHEXYLIDENEACETIC g ACIDS AND INTERMEDIATES 7 Claims, No DrawingsABSTRACT: Cyclohexanone, optionally substituted in the 2- 52 US. Clposition by lower-alkyl and/or m the 4Posmon by hydroxy or 1 260/2472 Bg' g ggggg acyloxy, reacts with a trilower-alkyl a-phosphono-lower-al-260/295 5 R 260/469 R 260/471 260/472 kanoate to give a lower-alkyl A,-cyclohexaneacetate or cor- 260/473 260/476 260/477 260/5 respondingderivative thereof. The latter is hydrolyzed to the 260/52l'A 260526;};260/540R 424/305 free acid, which, via the acid chloride, is esterifiedwith an 5| Int. Cl I cti7c 69/74 giving basic having cardimascu' 50Field at Search 260/468 and amidep'essam pmper'ies' BASIC ESTERS FCYCLOHEXYLIDENEACETIC ACIDS AND INTERMEDIATES This invention relates tomonocyclic substituted acids and esters thereof, and is in particularconcerned with basic esters of substituted cyclohexylideneacetic acidsand with intermediates therefor.

The compounds of the invention are of the fonnula wherein R isamino-lower-alkyl; R and R are hydrogen or lower-alkyl; and Z is CH O=C,(HO)CH, or (acylO)Cl-l.

The term lower-alkyl" used above in defining the groups R, R and Rstands for alkyl groups having up to about six carbon atoms, includingsuch groups as methyl, ethyl, propyl, isopropyl, butyl, hexyl, and thelike.

When R in formula 1 stands for an amino-loweralkyl group, it representsa lower-alkyl group substituted by a basic amino group. The exact natureof the basic amino moiety is not critical, although it is preferred thatit have a molecular weight less than about 200. A particularly preferredtype of amino-loweralkyl group has the structure -Y-N=B wherein Y islower-alkylene of two to five carbon atoms and N= B is unsubstitutedamino, lower-alkylamino, di-lower-alkylamino, polymethylenimino of fiveto seven ring carbons and lower-alkylated derivatives thereof,4-morpholinyl and lower-alkylated derivatives thereof, or l-piperazinyland lower-alkylated derivatives thereof. The term lower-alkyl" as usedin defining portions of the amino moiety N=B stands for alkyl groupshaving up to about six carbon atoms.

When 2 in formula I above stands for (acyl0)CH, the acyl groups arecarboxylic acyl groups having from one to 12 carbon atoms and molecularweights less than about 250. Representative of the lower-carboxylic acylradicals which can be present are lower-alkanoyl, e.g., acetyl,propionyl, isobutyryl, caproyl, heptanoyl, octanoyl, dodecanoyl,trimethylacetyl, and the like; cycloalkyl-lower-alkanoyl whereincycloalkyl has five to six ring members, e.g., B- cyclopentylpropionyl,B-cyclohexylpropionyl, and the like; benzoyl; phenyl-lower-alkanoyl or-alkenoyl, e.g., phenylacetyl, B-phenylpropionyl, cinnamoyl, and thelike; phenoxy-lower-alkanoyl, e.g., p-chlorophenoxyacetyl; carbamyl,including unsubstituted carbamyl, N-lower-alkylcarbamyl, N-phenylcarbamyl and N,N di-lower-alkylcarbamyl; and pyridylcarbonyl,e.g., nicotinoyl and isonicotinoyl. ln acyl radicals containing a phenylgroup, the benzene ring thereof can be unsubstituted or substituted byany number and kind of substituents inert under the reaction conditionsused, including lower-alkyl, e.g., p-tolyl; lower-alkoxy, e.g.,3,4-dimethoxy-phenyl; halogen (including fluorine, chlorine, bromine andiodine), e.g., 2-bromophenyl; and nitro, e.g., p-nitrophenyl. Thelower-alkyl and lower-alkoxy groups preferably have from one to fourcarbon atoms.

The compounds of formula l are prepared by esterification of compoundsof the formula wherein R, R and Z have the meanings given above and R"is hydrogen, by employing the appropriate amino-lower-alkanol oramino-lower-alkyl halide.

A preferred method comprises reacting the acid halide (e.g., chloride orbromide) of a free acid of formula II with atertiary-amino-lower-alkanol, although an alternative procedure involvesreacting an alkali metal salt (e.g., sodium salt) of the acid with anamino-lower-alkyl halide (e.g., chloride or bromide). Surprisingly, theacid halide process can be used even in the presence of a free hydroxygroup [Z (HO)CH]. it appears that if reaction does occur at the hydroxygroup during acid chloride formation, the hydroxy group is regeneratedduring the preparation of the basic ester.

The compounds of formula II wherein R" is hydrogen are in turn preparedby alkaline hydrolysis of the compounds of formula ll wherein R" islower-alkyl.

The compounds of formula ll wherein R" is lower-alkyl and Z is CH (HO)CHor (acyl0)CH are in turn prepared by reacting a compound of the formulawherein R is hydrogen lower-alkyl and Z is CH (HO)CH or (acyl0)CH with atri-lower-alkyl a-phosphono-lower-alkanoate of the formula .7 RIO in thepresence of a basic compound capable of acting as a proton acceptor.Examples of such basic compounds are alkali metal alkoxides, amides orhydrides, e.g., sodium methoxide, sodium amide or sodium hydride, andthe reaction is preferably carried out in nonaqueous medium at ordinarytemperatures.

The compounds of formula I! wherein R" is lower-alkyl and Z is O =C areprepared by oxidation of the corresponding compound wherein Z is (HO)CH,as by the action of chromic acid in pyridine solution.

The structures of the compounds of the invention were established by themodes of synthesis, by elementary analysis, by interpretation of theirinfrared, ultraviolet and NMR spectra, and by their behavior in thinlayer chromatography (TLC) and gas-liquid phase chromatography (glpc).

The compounds of formula I are basic in nature and form acid-additionsalts with moderate to strong inorganic or organic acids. Saidacid-addition salt forms are within the purview of the invention and areconsidered the full equivalents of the corresponding free bases. Forpharmacological purposes it is preferred to use water-soluble,pharmaceutically acceptable acid-addition salts, although allacid-addition salts are useful as characterizing derivatives of and asintermediates in the purification of the free bases.

Phannacological evaluation of the basic ester compounds of the inventionhas shown that they possess cardiovascular activity. They caused adecrease in the heart rate and contractile force in the isolated rabbitheart at dose levels of 50-100 gamma. There was also observed anantidepressant action in the compounds when tested for their ability toreverse reserpine induced ptosis in mice. The compounds are prepared foruse in the form of a sterile aqueous solution of a water-soluble,pharrnaceutically acceptable acid-addition salt.

Chemotherapeutic evaluation has shown that the compounds of formula Ialso possess antibacterial and antifungal activity when tested in vitroagainst the organisms Staph. au reus, E. typhi, CI. welchii, As. niger,M. albicans and the like.

The following examples will further illustrate the invention without thelatter being limited thereby.

EXAMPLE 1 Ethyl 4-hydroxy-A" -cyclohexaneacetate [I]; R" is C H R and Rare H, 2 is (HO)Cl-i] Sodium hydride (9.80 g., 50 percent in oil) wasadded to 400 ml. of dry dimethylformamide and cooled at 20 C. To thismixture 45.6 g. of triethyl phosphonoacetate was added dropwise whileholding the temperature below 20 C. When the addition was completed, themixture was stirred for 1 hour at room temperature, and then 24.16 g. of4-hydroxycyclohexanone was added dropwise while holding the temperaturebelow 30 C. About 1 hour after the addition of the4-hydroxycyclohexanone was completed, 1,600 ml. of water was added andthe mixture was extracted with ether. The ether extracts were washedwith sodium chloride solution, dried over anhydrous sodium sulfate andevaporated on a steam bath. The residue was distilled and the portionwhich boiled at l l4-142 C. (0.1 mm.) was collected. The latter waschromatographed on 800 g. of silica gel using 1:1 ether-pentane forelution. The eluted product was distilled to give 26.0 g. of ethyl4-hydroxy- A -cyclohexaneacetate, b.p. l l9-l2lC. (0.3 mm.).

Similarly, cyclohexanone and 2-methylcyclohexanone reacted with triethylphosphonoacetate to give ethyl A cyclohexaneacetate and ethyl2-methy1-A' -cyclohexaneacetate, respectively.

By replacing the triethyl phosphonoacetate in the foregoing preparationby a molar equivalent amount of trimethyl aphophonopropionate ortrimethyl a-phosphono-valerate, there can be obtained, respectively,methyl 4hydroxy-A- cyclohexanepropionate [11; R and R are CH R is H, Zis (HO)CH] or methyl 4-hydroxy-A -cyclo-hexanevalerate [11; R" is CH Ris C;,H,, R is H, 2 is (HO)CH].

Ethyl 4-hydroxy-A" -cyclohexaneacetate can be caused to react withacetic anhydride in pyridine to give ethyl 4-acetoxy-A"-cyclohexaneacetate [11; R" is C H R and R are H, 2 is (CH,COO)CH].

Ethyl 4-hydroxy-A"-cyclohexaneacetate can be oxidized by treating itwith chromic oxide in pyridine solution to give ethyl 4-oxo-A-cyclohexaneacetate 11; R is can, R and R are H, 2 is =C].

Ethyl 4-hydroxy-A" cyclohexaneacetate can be caused to react with phenylisocyanate to give ethyl 4-(N-phenylcarbamoyloxy)-A""-cyclohexaneacetate[11; R is C,H,,, R and R are H, 2 is (C,H,NHCOO)CH].

EXAMPLE 2 4-Hydroxy-A'-"-cyclohexaneacetic acid [11; R, R and R are H, 2is (HO)CH] A mixture of 21.65 g. of ethyl 4-hydroxy-A"-cyclohexaneacetate, 360 ml. of ethanol and 90 ml. of 2N sodiumhydroxide was refluxed for 90 minutes. The solvent was removed in vacuoand the residue was partitioned between water and ether. The aqueouslayer was acidified with 6N hydrochloric acid. The product whichseparated was collected and recrystallized from ethyl acetate to give4-hydroxy-A"-- cyclohexaneacetic acid, m.p. l50-l 52 C.

Similarly, ethyl A" -cyclohexaneacetate and ethyl 2- methyl-A'cyclohexaneacetate were hydrolyzed to give A cyclohexaneacetic acid and2methyl-A -cyclohexane-acetic acid, respectively.

The following acids can also be prepared by similar hydrolysis of thecorresponding lower-alkyl esters:

4-Hydroxy-A'-"-cyclohexanepropionic acid [11; R is 1-1, R is CH R is H,Z is (HO)CH],

4-Hydroxy-A" -cyclohexanevaleric acid [11; R is H, R" is C H R is H, 2is (HO)CH],

4-Oxo-A- -cyclohexaneacetic acid [11; R", R and R are H, 2 is O=C],

4-( N-Phenylcarbamoyloxy )-A- cyclohexaneacetic [11; R, R" and R are H,2 is (C,,H -,NHCOO)CH].

acid

EXAMPLE 3 Z-Dimethylaminoethyl 4-hydroxy-A- cyclohexaneacetate [1; R isCH,CH,N(CH R and R are H, 2 is HO)C1-1] 4-Hydroxy-A'- -cyclohexaneaceticacid (16.5 g.) was dissolved in ml. of methanol, 53 ml. of 2N sodiumhydroxide was added, and the mixture was evaporated to dryness in vacuoon a steam bath. Dry benzene (50 ml.) was added to the residue, themixture concentrated to dryness, and this procedure was repeated twicemore to ensure absence of water. Dry benzene (50 ml.) was introduced,and to the stirred mixture was added 39 ml. of oxalyl chloride dropwisewith occasional cooling of the reaction mixture. After the addition wascompleted, the mixture was kept at room temperature for about 45 minutesand the solvent was then removed in vacuo at below 50 C. To the residuewas added 50 ml. of dry benzene followed by dropwise addition of 49 g.of 2- dimethylaminoethanol while the mixture was stirred and cooled. Thereaction mixture was then warmed to about 50 C. for 30 minutes, cooledto room temperature, and 200 ml. of 2N ammonium hydroxide and 60 g. ofsodium chloride were added. The mixture was extracted with ether, andthe ether extracts were dried over anhydrous sodium sulfate andconcentrated. The product was purified in two portions by partitionchromatography using 360 g. of infusorial earth for each portion. Therewas thus obtained Z-dimethylaminoethyl 4- hydroxy-A -cyclohexaneacetatein the form of its hydrochloride salt, colorless needles, mp. l63.5166C. when recrystallized from acetonitrile.

By replacing the Z-dimethylaminoethanol in the foregoing preparation bya molar equivalent amount of 3-dibutyl' aminopropanol. 2-(l-piperidyl)ethanol, 2( l-pyrrolidyl)- ethanol,2-(4-morpholinyl)ethanol, 2-(4-methyl-l-piperidyl)- ethanol, or2-(4-methyl-l-piperazinyl)ethanol, there can be obtained respectively,3-dibutylaminopropyl-4-hydroxy-A"- cyclohexaneacetate [1; R is CH CH,CHN(C H,) R and R are H, Z is (HO)CH], 2-(l-piperidyl)ethyl 4-hydroxy-A"cyclohexaneacetate [1; R is CH,CH N(CH,) R and R are H, 2 is (HO)CH],2-( l-pyrrolidyl)ethyl 4-hydroxy-A"- cyclohexaneacetate [1; R isCH,CH,N(CH R" and R are H, 2 is (HO)CH], 2-(4-morpholinyl)ethyl4-hydroxy-A"- cyclohexaneacetate [1; R is CH,CH,N(CH,),O, R and R are H,2 is (HO)CH], 2-(4-methyl-l-piperidyl)ethyl 4-hydroxy- A-cyclohexaneacetate [1; R is CH,CH,N(CH,) CHCH,, R and R are H, 2 is(HO)CH], or 2-(4-methy1-l-piperazinyl)- ethyl 4-hydroxy-A"-cyclohexaneacetate [1; R is CH,CH N( CH NCH R and R are H, 2 is(HO)CH].

Similarly, 4-hydroxy-A"-cyclohexanepropionic acid, 4- hydroxy-A"-cyclohexanevaleric acid, 4-oxo-A -cyclohexaneacetic acid or4-(N-phenylcarbamoyloxy)-A" -cyclohexaneacetic acid can be esterified togive, respectively, 2- dimethylaminoethyl 4-hydroxy-A"-cyclohexanepropionate [1; R is CH CH N(CH R" is CH R is H,Zis(HO)C1-1], 2- dimethylaminoethyl 4-hydroxy-A -cyclohexanevalerate [1;R is CH,CH N(CH R is C H R is H, 2 is (HO)CH], 2- diethylaminoethyl4-oxo-A" -cyclohexaneacetate [1; R is CH C1-1 N(CH R and R are H, Z isO=C], or 2- diethylaminoethyl 4-(N-phenylcarbamoyloxy)-A"-cyclohexaneacetate [1; R is CH CH N(CH R and R are H, Z is (C HNHCOO)CH].

Z-Dimethylaminoethyl 4-hydroxy-A" *-cyclohexanepropionate can be causedto react with acetic anhydride, caproyl chloride, benzoyl chloride,p-methoxybenzoyl chloride, B-cyclopentylpropionyl chloride, cinnamoylchloride or nicotinoyl chloride in pyridine solution to give,respectively, the 4-acetate, 4-caproate, 4-benzoate,4-(pmethoxybenzoate) 4-(B-cyclopentylpropionate), 4-cinnamate or4-nicotinate of Z-dimethylaminoethyl 4-hydroxy-A"- 4cyclohexanepropionate.

EXAMPLE 4 The solvents were removed by warming under reduced pressureand the residue was dissolved in 300 ml. of dry benzene.2-Dimethylaminoethanol (60 ml.) was added dropwise with stirring andcooling and the resulting mixture was then heated under reflux for 2hours. The mixture was cooled, diluted with 2 liters of ether andextracted twice with 2N hydrochloric acid, the second extracts beingstrongly acidic. The combined extracts were made alkaline with 35percent sodium hydroxide with cooling and the liberated base wascxtructed with ether. These ether extracts were washed with water andbrine, dried (MgSO and concentrated to give 37.3 g. of brown, oily basicester. A solution of this oil in 500 ml. of ether was treated with 20.4ml. of 8.7N ethanolic hydrogen chloride and the precipitate wascollected and recrystallized from acetone to give 35.0 g. (64 percent)of Z-dimethylaminoethyl A cyclohexaneacetate in the form of itshydrochloride salt, m.p. 172 -l74 C. One further recrystallization fromacetone gave a sample with the m.p. l73l 74 C.

EXAMPLE 5 Z-Dimethylaminoethyl 2-methyl-A'--cyclohexaneacetate [l; R isCH CH N(CH R is CH R is H, Z is CH was prepared from Z-methyI-A"-cyclohexaneacetic acid and 2- dimethylaminoethanol by the proceduredescribed above in example 4. There was thus obtainedZ-dimethylaminoethyl 2- methyl-A-'-cyclohexaneacetate in the form of itshydrochloride salt, m.p. l29l3l C. (needle clusters from acetone).4-Hydroxy-A" -cyclohexaneacetic acid can be converted to the sodium saltwith one equivalent of sodium methoxide in dimethylsulfoxide solution,and said sodium salt then caused to react with benzyl2-bromoethylcarbamate or benzyl (N- methyl)-2-bromoethylcarbamate togive, respectively, 2-(carbobenzoxyamino)-ethyl 4-hydroxy-A"-cyclohexaneacetate or 2-[carbobenzoxy-(N-methyl)-amino]-ethyl4-hydroxy-A"- cyclohexaneacetate. The latter two compounds, when treatedwith trifluoroacetic acid, one day at room temperature, can beconverted, respectively, to 2-aminoethyl 4-hydroxy-A""-cyclohexaneacetate [1; R is CH CH NH R and R are H, Z is (HO)CH], or2-methylaminoethyl 4-hydroxy-A -cyclohexaneacetate [1; R is CH CH NHCH Rand R are H, Z is HO)Cl-l].

We claim: 1. A compound ofthe formula CH CH R =o-c OOR CH CH wherein Ris amino-lower-alkyl, R and R are hydrogen or lower-alkyl; and Z is CH,,O=C, (HO)CH or (acyl0)CH, acyl being selected from the group consistingof lower-alkanoyl of up to 12 carbon atoms, cycloalkyl-lower-alkanoylwherein cycloulkyl has five to six ring members, benzoyl,phenyllower-ulknnoyl, phenyl-lowcr-nlkcnoyl, phcnoxy-lowcr-nL kunoyl,curbnmyl, N-|owcr-ulkylcurbumyl. N-phenylcurhumyl,N,N-di-lower-ulkylcurbamyl. nicotinoyl and isonicotinoyl, and whereinthe phenyl group of any of the acyls can be unsubstituted or substitutedby lower-alkyl, lower-alkoxy, halogen or nitro.

2. Z-Dimethylaminoethyl A" -cyclohexaneacetate, according to claim 1,wherein R is Z-dimethylaminoethyl, R and R are hydrogen and Z is CH 3.Z-Dimethylaminoethyl 2-methyl-A -cyclohexaneacetate, according to claim1, wherein R is 2- dimethylaminoethyl, R is hydrogen, R is methyl and Zis CH 4. 2-Dimethylaminoethyl 4-hydroxy-A -cyclohexaneacetate, accordinto claim I, wherein R is 2- dimethylaminoethyl, and R are hydrogen and Zis (HO)CH.

5. A compound of the formula CH,CH, R

Z\ C=CCOOR CHICH wherein R, R and R" are hydrogen or lower-alkyl, and Zis O C, (HO)CH or (acyl0)CH, acyl being selected from the groupconsisting of lower-alkanoyl of up to 12 carbon atoms,cycloalkyl-lower-alkanoyl wherein cycloalkyl has five to six ringmembers, benzoyl, phenyl-lower-alkanoyl, phenyl-loweralkenoyl,phenoxy-lower-alkanoyl, carbamyl, N-lower-alkylcarbamyl,N-phenylcarbamyl, N,N -di-lower-alkylcarbamyl, nicotinoyl andisonicotinoyl, and wherein the phenyl group of any of the acyls can beunsubstituted or substituted by loweralkyl, lower-alkoxy, halogen ornitro.

6. Loweralkyl 4-hydroxy-A-"-cyclohexaneacetate, according to claim 5,wherein R and R are hydrogen, R" is loweralkyl and Z is (HO)CH.

7. 4-Hydroxy-A -cyclohexaneacetic acid, according to claim 5, whereinR", R and R are hydrogen and Z is (HO)CH.

P040510 UNITED STATES PATENT OFFICE 569 CERTIFICATE OF CORRECTION PlateN- 1624-127 1 Dated Inventor(s) Philip E. Shaw, Sol J. Dawn and RobertL. Clarke It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Cover page, second column, line t of abstract, "A should read --A KColumn 1, in formula I, R" should read --R--. Column 3, line 26, line57, line 74 and Column 4, line Mt, line 52 and line 54, "A should read-'A (each occurrence).

Column 3, line 65, R should read --R"--.

Column 6, line 3 Claim 5, '0" should read --o-= Signed and sealed this30th day of May 1972.

(SEAL) Attest:

ROBER GOI'ISCHAL K EDWARD M.FLETCHER, JR.

Commie s ioner of Patents Attesting O fficer

2. 2-Dimethylaminoethyl Delta 1, -cyclohexaneacetate, according to claim1, wherein R is 2-dimethylaminoethyl, R* and R'' are hydrogen and Z isCH2.
 3. 2-Dimethylaminoethyl 2-methyl- Delta 1, -cyclohexaneacetate,according to claim 1, wherein R is 2-dimethylaminoethyl, R* is hydrogen,R'' is methyl and Z is CH2.
 4. 2-Dimethylaminoethyl 4-hydroxy- Delta 1,-cyclohexaneacetate, according to claim 1, wherein R is2-dimethylaminoethyl, R* and R'' are hydrogen and Z is (HO)CH.
 5. Acompound of the formula wherein R*, R'' and R'''' are hydrogen orlower-alkyl, and Z is O C, (HO)CH or (acylO)CH, acyl being selected fromthe group consisting of lower-alkanoyl of up to 12 carbon atoms,cycloalkyl-lower-alkanoyl wherein cycloalkyl has five to six ringmembers, benzoyl, phenyl-lower-alkanoyl, phenyl-lower-alkenoyl,phenoxy-lower-alkanoyl, carbamyl, N-lower-alkylcarbamyl,N-phenylcarbamyl, N,N-di-lower-alkylcarbamyl, nicotinoyl andisonicotinoyl, and wherein the phenyl group of any of the acyls can beunsubstituted or substituted by lower-alkyl, lower-alkoxy, halogen ornitro.
 6. Lower-alkyl 4-hydroxy- Delta 1, -cyclohexaneacetate, accordingto claim 5, wherein R* and R'' are hydrogen, R'''' is lower-alkyl and Zis (HO)CH.
 7. 4-Hydroxy- Delta 1, -cyclohexaneacetic acid, according toclaim 5, wherein R*, R'' and R'''' are hydrogen and Z is (HO)CH.